Medical Journal Review
Posted: October 2010
Reviewed by Juan Carlos Ivancevich, MD, in collaboration with Phil Lieberman, MD.
1. Intermediate Phenotypes in Asthma Using Bronchoalveolar Lavage-Derived Cytokines
The authors applied a heuristic analysis of the phenotypic parameters and physiological data from 1,048 subjects enrolled in the US Severe Asthma Research Program (SARP) to identify four largely separable, quantitative intermediate phenotypes. They defined subgroups as extremes in bronchoalveolar lavage (BAL) cellularity (eosinophils, and neutrophils), enhanced bronchodilator response ("bronchodilators"), and methacholine sensitivity ("hyperresponders"). Inter-group relationships determined by network analysis showed these four groups to be largely distinct. Next the authors identified the optimal statistical learning approaches that best predict these intermediate phenotypes from BAL cytokines using logistic regression (LR), multivariate adaptive regression splines (MARS), classification and regression trees (CART), and random forest (RF) classifiers. Despite distinct assumptions about the relationship between features (cytokines) and outcomes (intermediate phenotypes), both LR and MARS approaches were comparable in accuracy and Receiver Operating Curve (ROC) characteristics and both outperformed CART and RF. These results suggest the optimal statistical learning approaches for using multidimensional protein profiling to phenotypes in investigation of airways disease. An important problem in realizing personalized medicine is the development of methods for identifying disease subtypes using quantitative proteomics. These robust classification methods will aid future translational studies in asthma targeted at specific intermediate phenotypes.
Editor's comment: These assays can be adapted to breath condensate analysis for larger scale clinical application.
Brasier AR, Víctor S, Ju H et al. Predicting Intermediate Phenotypes in Asthma Using Bronchoalveolar Lavage-Derived Cytokines. Clinical and Translational Science 2010; 3(4):147-157.
2. Group C human rhinoviruses (HRVC) implicated in most childhood asthma attacks
To investigate the new and potentially more pathogenic group of HRV, group C, which may be associated with more severe asthma attacks than HRV group A or B viruses or other viruses, the researchers studied 128 children, aged 2-16 years, from the Perth Childhood Acute Asthma Study who attended an emergency department suffering from asthma attacks. The severity of the children's asthma exacerbations was assessed, and nasal secretions were collected for analysis of respiratory viruses. Most of the children (85.2%) had moderate-to-severe asthma and 98.9% were admitted to hospital. Overall, 87.5% of the children showed evidence of HRV infection, including most of the 14.8% of children that showed evidence of infection with other viruses. Furthermore, more than half (59.4%) of the children were infected with HRVC, which was associated with increased asthma severity. Indeed, children with HRVC had significantly higher mean asthma exacerbation severity scores than those infected with HRV A or B only (n=34), at 10.4 versus 9.5, and all other children who were not infected with an HRVC strain (n=50), at 9.4. These differences in severity remained significant after adjustment for age and gender. The current study has shown that the newly identified HRVC group of viruses is responsible for not only the majority of acute asthma attacks in children, but also that this group causes more severe attacks than previously-known viruses.
Editor's comment: These findings suggest that HRVC is by far the most important strain of virus associated with episodes of acute asthma.
Bizzintino J , Lee W-M, Laing IA et al. Association between human rhinovirus C and severity of acute asthma in children. European Respiratory Journal. [Published online before print 6 August 2010. doi: 10.1183/09031936.00092410]
3. New guidelines for diagnosing and managing anaphylaxis
The guidance was developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology. The paper published version reviewed here is an abbreviated executive version, and the entire document is available on line. It draws attention to some new developments. For example, anaphylactic reactions can be the result of cascades other than mast cell/basophil-derived mediators. As such, there have been reports of patients not responding to "classical therapy" with epinephrine, but to tranexamic acid (if anaphylaxis is linked with intravascular coagulation) and methylene blue (in cases with hypotension, to inhibit the synthesis of nitric oxide). Another highlighted point is that patients who become hypotensive should remain recumbent until the cardiovascular system has been stabilized and they are completely asymptomatic. Deaths, associated with assuming the upright sitting position prematurely, have occurred. In the 2010 update the authors reviewed numerous specific triggers for anaphylaxis. Food allergens account for 30% of fatal cases of anaphylaxis. Asthma is a risk factor for severe food allergy, and biphasic anaphylactic reactions can occur in up to 25% of fatal and near-fatal food reactions. Latex and anesthesia are other common triggers. Coital anaphylaxis due to seminal fluid is another possibility. For patients with exercise-induced anaphylaxis, prophylactic medications are usually not effective, but attacks appear to become less frequent and severe over time. Other triggers covered include insect stings, drugs and biological agents, and allergens used in immunotherapy. As for prevention, the report notes that avoidance has to be tailored to the individual, based on considerations of age, occupation, residential conditions, etc. The authors advise that patient education might be the most important preventive strategy. They recommend that anyone who's had an episode of anaphylaxis be taught to self-administer the medication.
Editor's comment: Excellent update on an allergic condition that can cause life-threatening.
Lieberman P, Nicklas RA, Oppenheimer J et al. The diagnosis and management of anaphylaxis practice parameter: 2010 Update. Journal of Allergy and Clinical Immunology. 2010; 126(3):477-480 e.42.
4. Acetaminophen use in childhood may be an important risk factor for the development and/or maintenance of asthma.
To investigate the risk of asthma and other allergic disorders associated with the current use of acetaminophen in 13 to 14 year old children in different populations worldwide, as part of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three, 13 to 14 year old children were asked to complete written and video questionnaires to obtain data on current symptoms of asthma, rhinoconjunctivitis and eczema. In addition a written environmental questionnaire on putative risk factors, including acetaminophen use in the past 12 months, was completed. The primary outcome measure was the odds ratio (OR) of current asthma symptoms associated with acetaminophen use calculated by logistic regression. A total of 322,959 adolescent children from 113 centers in 50 countries participated. In the multivariate analyses the recent use of acetaminophen was associated with an exposure-dependent increased risk of current asthma symptoms [OR 1.43 (95% CI 1.33 to 1.53) and 2.51 (95% CI 2.33 to 2.70) for medium and high versus no use respectively]. Acetaminophen use was also associated with an exposure-dependent increased risk of current symptoms of rhinoconjunctivitis and eczema. The authors concluded that acetaminophen use may represent an important risk factor for the development and/or maintenance of asthma, rhinoconjunctivitis and eczema in adolescent children.
Editor's comment: It is not possible in a study of this design to determine whether the positive association observed was causal, so randomized controlled trials are required to investigate this relationship.
Beasley RW, Clayton TO, Crane J et al. Acetaminophen Use and Risk of Asthma, Rhinoconjunctivitis and Eczema in Adolescents: ISAAC Phase Three. American Journal of Respiratory and Critical Care Medicine. [Published online ahead of print 2010 doi:10.1164/rccm.201005-0757OC]
5. Vitamin D may treat or prevent allergy to Aspergillus fumigatus (Af).
The researchers wanted to identify the factors that determine why only a subset of patients develop allergy and what factors regulate tolerance or sensitization to Af resulting in the development of Allergic Bronchopulmonary Aspergillosis (ABPA). To gain insights, the group studied two groups of patients with Cystic Fibrosis (CF). Both groups were colonized with Af, but only one had ABPA. The researchers focused on Th2 cells. They found that a protein called OX40L was critical in driving Th2 responses to Af in the CD4+T cells isolated from patients with ABPA and that this group had a much greater Th2 response to Af. The CD4+T cells from the group of patients that did not have ABPA had higher levels of the proteins, FoxP3 and TGF-ß,both of which are known to be critical to the development of allergen tolerance. The researchers discovered that heightened Th2 reactivity in the ABPA group correlated with a lower average blood level of vitamin D. They found that adding vitamin D not only substantially reduced the production of the protein driving an allergic response, but it also increased production of the proteins that promote tolerance.
Editor's comment: The next step is to conduct a clinical trial to see if vitamin D can be used to treat or prevent this complication of asthma and cystic fibrosis.
Kreindler JL, Steele C, Nguyen N et al. Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis. Journal of Clinical Investigation 2010; 120(9):3242.
6. Pitfalls in the diagnosis of latex allergy.
The authors of this paper point out that screening patients for latex allergy prior to surgery is an important but intensive procedure, and that the sensitivity and specificity of both skin and serum tests can be influenced by patient-specific factors or manufacturing processes that alter the clinically relevant allergens in skin testing solutions. In this study, total IgE and latex-specific IgE testing was utilised as a screening test. Skin prick testing was done on patients with a high probability of latex allergy and negative specific IgE with total IgE <100kU/L. Non-ammoniated latex (NAL) and newly introduced ammoniated latex (AL) reagents were assessed for the clinically relevant allergens. 51 patients had a total IgE <100 (range, 2.8-99.0kU/L), and 10% had a positive skin test. 60% of positive skin tests would have been missed with lower total IgE cut-offs of 50kU/L (6% of referrals). SDS-PAGE of the NAL solution showed 3 prominent bands with molecular weights of approximately 20, 24 and 42kDa that correlated with Hev b 6, Hev b 3 and Hev b 7/13, respectively. In contrast, the AL solution showed 3 very faint higher molecular weights bands that did not correlate with clinically relevant antigens. The authors conclude that increasing the cut-off value of total IgE for allergen-specific IgE testing increased the sensitivity of the specific IgE test. The NAL reagent had a greater number of clinically significant allergens at higher concentrations than AL, which may have implications for the clinical sensitivity of the newer AL reagent.
Editor's comment: It should have tests sensitive and specific enough to determine the latex allergy and avoid false negatives and / or positives.
Khan S, Holding S, Dore P, et al. Pitfalls in the diagnosis of latex allergy. Allergology International 2010; 59(3):305-308.
7. Identification of a genetic basis for determining the severity of allergic asthma in an experimental model.
The authors identify the pro-inflammatory protein, interleukin-17 (IL-17A), as the chief culprit behind severe asthma-like symptoms in mice. The study involved mice bred genetically to closely resemble people susceptible to severe asthma. Mouse airways were exposed to house dust mite allergen extract to gauge the severity of disease and analyze biochemical responses in airway tissues. One group of mice was deficient in the immune system gene C5, which normally prevents harmful airway immune responses to inhaled environmental allergens. These mice generated high numbers of TH17 cells that produced significant IL-17A and caused airway hyper-responsiveness. When researchers blocked IL-17A production in this group, the mice had less airway hyper-responsiveness. A second group of mice was deficient in the C3aR gene (a receptor for C3), which regulates the dysfunctional response to airway allergens that lead to asthma. These mice had fewer IL-17A producing TH17 cells and less airway hyper-responsiveness. When researchers increased the amount of IL-17A in the airways of this group, the mice experienced greater airway hyper-responsiveness.
Editor's comment: This study suggests that at some point it may be possible to treat or prevent severe forms of asthma by inhibiting pathways that drive the production of IL-17A.
Lajoie S, Lewkowich IP, Suzuki Y et al. Complement-mediated regulation of the IL-17A axis is a central genetic determinant of the severity of experimental allergic asthma. Nature Immunology 2010; 11(10):928-935.
8. Increased expression of high-affinity immunoglobulin (Ig)E receptor (FcεRI) in airways of fatal asthma (FA) attack patients.
To investigate the distribution of FcεRI expression in the airways and within the airway wall, the authors studied postmortem tissue samples taken from the small (SA) and large (LA) airways of 24 non-smokers and 13 smokers with FA, and from 19 patients who died of non-pulmonary causes (controls). Immunohistochemical staining was used to assess expression of FcεRI and mast cell tryptase marker AA1 in the inner and outer layers of both SA and LA. The researchers found that FcεRI expression was higher in the inner and outer layers of SA tissue taken from non-smokers and smokers with FA compared with SA tissue from controls. FcεRI expression was higher in the outer layer of LA tissue from non-smokers with FA only, compared with that from controls. They also found that AA1 expression was higher in the outer layer of SA tissue from non-smokers with FA compared with that from smokers with FA and controls, and this correlated with FcεRI expression in this layer. These findings on the expression of FcεRI in the SA imply that the IgE-mediated reactions against allergens might also occur at this location, besides the well-established reaction in LA. The authors concluded that inflammation caused by IgE-mediated reactions in SA might contribute to tissue destruction and airway remodeling, which could lead to small airways dysfunction.
Editor's comment: Targeting the activation of FcεRI to treat asthma might dampen IgE-mediated inflammatory reactions and its downstream processes such as airway remodeling in both LA and SA.
Otter D, Silva I, Carvalho, LFF et al. High-affinity immunoglobulin E receptor expression is increased in large and small airways in fatal asthma. Clinical & Experimental Allergy 2010; 40(10): 1473-1481.
9. Sleep apnea risk linked to asthma control.
To investigate if unrecognized OSA may lead to poor asthma control despite optimal therapy, the authors studied 472 patients with asthma, aged 18 to 75 years, who received asthma treatment between 2007 and 2009. All of the patients completed the Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ), which assigns scores on a severity scale of 1-5 for eight OSA symptom items, including loud snoring disruptive to the bed partner, breathing pauses during sleep, and sudden gasping arousals. They also completed the Asthma Control Questionnaire (ACQ), which rates asthma control on a scale of 1.0-7.0, with 1.0 representing adequately controlled asthma. High risk for OSA was defined by an SA-SDQ score of at least 36 for men and at least 32 for women, and not-well-controlled asthma in both genders was defined by an ACQ score of at least 1.5. In total, 80 (17%) patients had not-well-controlled asthma, and 109 (23%) were at high risk for OSA. After accounting for demographic variables and factors known to affect asthma control, such as obesity and gastro-esophageal reflux disease, the researchers found that patients at high risk for OSA were 2.87 times more likely to have not-well-controlled asthma than those at low risk for OSA. The researchers concluded that these data strengthen the evidence of the role of OSA in asthma control, and suggest that OSA may prove to be a treatable target in patients affected by these highly prevalent and interacting conditions.
Editor's comment: Prospective studies with objective sleep assessments are needed to better understand this relationship and its mechanistic basis.
Teodorescu M, Polomis DA, Hall SV et al. Association of Obstructive Sleep Apnea Risk With Asthma Control in Adults. Chest 2010; 138(3): 543-550.
10. Combined IgE levels and airways disease severity score predict asthma in children.
The object of this study was to see if combining quantitative measures of IgE antibodies (Σ-IgE) with the severity score of obstructive airways disease (OAD) at 2 years of age (severity score) was superior to predict current asthma (CA) at 10 years than either measure alone. Secondarily,the authors wished to see if gender modified the prediction of CA.To do this a prospective birth cohort (Environment and Childhood Asthma) study was utilized. All children evaluated supplied blood samples for IgE antibody analysis at the age of 2 years. They were also assigned an OAD severity score (0-12, with 12 representing the most severe disease) based upon number of episodes, number of months, and number of hospital admissions because of bronchial obstruction at this age. By the age of 10 years, 219 children had recurrent bronchial obstruction (current asthma) while 152 did not. Analysis revealed that OAD severity score alone explained 24% of the variation in current asthma, while Σ-IgE alone explained only 6%. However, a combination of OAD severity score and Σ-IgE explained 30% of the variation in current asthma at the age of 10 years. Further analysis indicated that the OAD severity score predicted current asthma in both genders, but the predictive capacity of Σ-IgE was limited to boys. The authors concluded that the combination of the measurement of specific IgE antibodies to inhalant allergens and a severity score of OAD at 2 years was superior to predicting asthma 8 years later than either measurement alone. The IgE antibodies did, however, predict later asthma in boys only. Using these two factors may reasonably well predict individual risk of later asthma, but further studies in general populations are required to assess the predictive capacity of these measures.
Editor's comment: Combining quantitative measures of immunoglobulin (Ig)E antibodies (Σ-IgE) and obstructive airways disease (OAD) severity score at 2 years of age is better for predicting asthma at the age of 10 years than either measure alone.
Lødrup Carlsen KC, Söderström L, Mowinckel L et al. Asthma prediction in school children; the value of combined IgE-antibodies and obstructive airways disease severity score. Allergy 2010; 65(9): 1134-1140.